Adenosine deaminase (ADA) is a purine salvage enzyme that regulates the levels of adenosine and deoxyadenosine in mammalian tissues. Genetic deficiency of this enzyme is a cause of hereditary severe combined immune deficiency syndrome. A transgenic mouse model for adenosine deaminase deficiency has been produced that develops severe T cell deficiency. In addition, these transgenic mice manifest symptoms characteristic of asthma including eosinophilic inflammation of the lung, mucus overproduction, and airway obstruction. Since ample evidence ha previously shown that Th2 cells and their cytokines play a pivotal role in asthma pathogenesis, the asthma-like pathology present in our Th2-deficient mice points to some interesting Th2 cell-independent mechanism. To gain a better understanding of asthma pathogenesis in this novel animal model, we performed DNA microarray analyses. The results showed the absence of upregulation of Th2 cell-derived cytokines, and upregulation of a number of other cytokines/chemokines in the lung of ADA-negative mice. The genes that are expressed at the highest levels include TARC (thymus activated and regulated cytokine), JE/MCP- 1, KC/GRO 1, and eotaxin. Some of these genes are known to also play a role in allergic asthma, suggesting that adenosine-induced, Th2-independent asthma and Th2-mediated allergic asthma share common downstream pathways in disease pathogenesis. Our mouse model may also unmask certain mechanisms in allergic asthma, which were masked by the Th2-dependent mechanism. Bronchial epithelial cells are known to produce TARC and other chemokines. In this application, we propose to test the hypothesis that adenosine, a well-documented signaling molecule, induces the production of TARC, JE/MCP-1 KC/GRO1 and eotaxin by lung epithelial cells. We will further test the hypotheses that these effector molecules are the pathogenic factors in the development of asthma-like disease in our mouse model and that adenosine receptor blocker could prevent the disease process. This transgenic mouse line provides a unique opportunity for studying the mechanism of Th2 cell-independent asthma-like disease, and has great potential for use in developing novel therapeutics.